1. Field of the Invention
This invention relates to novel compounds which bind to the human erbB2 gene product (ErbB2, also known as HER2, or c-ErbB-2). In particular aspects, the invention relates to the treatment of disorders characterized by the expression of ErbB2 utilizing the novel compounds of the invention. The invention also relates to compositions, such as pharmaceutical compositions, comprising the novel compounds, as well as their use in research, diagnostic, therapeutic, and prophylactic methods.
2. Description of Related Disclosures
Phage display provides a means for generating peptides and protein variants through randomization of specific amino acid residues within a template sequence or by generation of naive peptide libraries (Lowman, H. (1998) Methods Mol. Biol. 87:249-264; Lowman (1997) Annu. Rev. Biophys. Biomol. Struct. 26:401-424). Identification and isolation of displayed proteins or peptides that bind a predetermined target molecule can be achieved through enrichment of displaying phage over non-binding or weakly binding variants on immobilized target molecules (Lowman, H. (1989), supra). Successive rounds of mutagenesis and selection can yield peptide ligands or protein variants with high affinity for cellular receptors (Lowman, H. (1998), supra). The technique has been used to identify peptide motifs that home to, for example, a cellular target (Arap et al., (1998) Science 279:377-380), or to generate affinity improved or matured peptide ligands from native protein binding ligands (Lowman et al., (1991) Biochemistry 30: 10832-10838). Examples of affinity or specificity improved proteins include human growth hormone, zinc fingers, protease inhibitors, atrial natriuretic peptides, and antibodies (Wells, J. and Lowman H. (1992) Curr. Opin. Struct. Biol. 2:597-604; Clackson, T. and Wells, J. (1994) Trends Biotechnol. 12:173-184; Lowman et al., (1991) Biochemistry 30(10):832-838; Lowman et al. and Wells J. (1993) J. Mol. Biol. 234:564-578; Dennis M. and Lazarus R. (1994) J. Biol. Chem. 269(22):137-144).
Utilizing in vivo phage selection, phage display has been used to identify and isolate peptides capable of mediating selective localization to various organs such as brain and kidney (Pasqualini and Ruoslohti (1996) Nature 380:364-366) as well as to identify peptides that home to particular tumor types bearing αvβ3 or αvβ5 integrins (Arap et al., (1998) Science 279:377-380). U.S. Pat. No. 5,627,263 describes peptides that are recognized by and selectively bind the αvβ1 integrin. Using structurally constrained peptide libraries generated by monovalent phage display, 14 amino acid peptides that specifically bind to insulin-like growth factor 1 binding proteins (IGFBPs) have been isolated (Lowman et al., (1998) Biochemistry, 37:8870-8878). The peptides contain a helix structure and bind IGFBPs in vitro liberating insulin like growth factor-α (IGF-1) activity (Lowman et al., (1998) supra).
Particular cellular receptors and their ligands, especially those implicated in the pathogenesis of various human malignancies, have recently been the focus of much attention in the scientific community as novel protein based therapeutics enter the clinic. For example, it has been found that the human erbB2 gene (also known as her2, or c-erbB-2), which encodes a 185-kd transmembrane glycoprotein receptor (p185HER2) related to the epidermal growth factor receptor (EGFR), is overexpressed in about 25% to 30% of human breast cancer (Slamon et al., (1987) Science 235:177-182; Slamon et al., (1989) Science 244:707-712). Several lines of evidence support a direct role for ErbB2 in the pathogenesis and clinical aggressiveness of ErbB2-overexpressing tumors. The introduction of erbB2 into non-neoplastic cells has been shown to cause their malignant transformation (Hudziak et al., (1987) Proc. Natl. Acad. Sci. USA 84:7159-7163; DiFiore et al., (1987) Science 237:78-182). Transgenic mice that express HER2 were found to develop mammary tumors (Guy et al., (1992) Proc. Natl. Acad. Sci. USA 89:10578-10582).
ErbB2 overexpression is commonly regarded as a predictor of a poor prognosis, especially in patients with primary disease that involves axillary lymph nodes (Slamon et al., (1987) and (1989), supra; Ravdin and Chamness, (1995) Gene 159:19-27; and Hynes and Stern, (1994) Biochim. Biophys. Acta 1198:165-184). Overexpression has also been linked to sensitivity and/or resistance to hormone therapy and chemotherapeutic regimens, including CMF (cyclophosphamide, methotrexate, and fluoruracil) and anthracyclines (Baselga et al., (1997) Oncology 11(3 Suppl 1):43-48).
A recombinant humanized anti-ErbB2 monoclonal antibody (a humanized version of the murine anti-ErbB2 antibody 4D5, referred to as rhuMAb HER2 or HERCEPTIN®) is therapeutically active in patients with ErbB2-overexpressing metastatic breast cancers that have previously received extensive anti-cancer therapy (Baselga et al., (1996) J. Clin. Oncol. 14:737-744).